The present invention relates to quinolone carboxylic acid-substituted rifamycin derivatives wherein a quinolone carboxylic acid antibiotic pharmacophore is covalently and chemically combined with a 3,4-fused rifamycin: a 3,4-fused benzoxazinorifamycin or a 3,4-fused spiropiperidineimidazolorifamycin, resulting in a multifunctional antibiotic possessing multiple antibacterial pharmacophores.
The increasing spread in bacterial resistance to existing antibacterial agents is a major clinical problem. Accordingly, there is a need in the art for compounds, compositions, and methods of treating warm-blooded animals that suffer from bacterial infections and are resistant to conventional antibacterial treatments. Rifamycin class of natural product derived antibiotics, like rifampin, rifabutin and rifapetine are currently used for the treatment of tuberculosis and other microbial infections (Farr, B. M., Rifamycins). At present, one of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of bacterial resistance. Mutations in rifamycin's target RNA polymerase are mainly responsible for the high frequency of development of resistance. Consequently, rifamycins are currently used only in combination therapies to minimize the development of resistance to this class of drug. Unfortunately, some antibiotic combinations are antagonistic, such as the rifampin and vancomycin combination (Watanakunakorn, 1981), and the rifampin and sparfloxacin combination (Yajko, D. M. 1990). Furthermore, even with co-administration of other antibiotics, resistance development to rifamycin component is frequent (Karchmer, A. W. 1983).
The 7-substituted quinolone carboxylic acids are well known as quinolone class of anti-bacterial agents and as synthetic intermediates to related compounds. The quinolone antibacterials including ciprofloxacin (U.S. Pat. Nos. 4,563,459 and 4,620,007); gatifloxacin and moxifloxacin (U.S. Pat. No. 5,880,283) are widely prescribed in clinic. The wide-spread use of these agents has resulted in high rate of resistance to this class of agents (Kaufman C. A. 1990), so that the compounds which are effective against quinolone resistant bacteria are highly desired.
U.S. Pat. No. 4,983,602 discloses a series of 3,4-benzoxazinorifamycins with various substituted piperazine groups. U.S. Pat. No. 4,219,478 discloses a series of 3,4-spiropiperidino-rifamycins with various alkyl groups. Neither patents disclose quinolone carboxylic acid substituted-rifamycin derivatives, their antibacterial activities and use of them for the treatment of infections. Published United States Patent Application Nos. US2005/0209210, US2005/0261262, US 2006/0019985 and US 2006/0019986 describe quinolone carboxylic acid substituted-rifamycin derivatives, wherein a quinolone carboxylic acid is linked to a rifamycin at C-3 position of rifamycin core-structure through variety of linkers, but not to a 3,4-fused benzoxazinorifamycin or a spiropiperidinorifamycin. Therefore, none of the patents or patent applications mention the linking quinolone-3-carboxylic acids to a 3,4-fused benzoxazinorifamycins or a 3,4-fused spiropiperidinorifamycins and their antibacterial activity and use of them as antibacterial agents for the treatment of infections.